There is an ever-increasing desire for combining active ingredients belonging to different therapeutic categories. However, instability of the active ingredients poses a major obstacle in combining these active ingredients in a single dosage form. Drug instability is the phenomenon, which occurs when the effects of one drug are modified by the presence of another drug in the same dosage form. Therefore, combination dosage form which combines the features of pharmacologic efficacy, adequate drug stability, and a reliable and robust method of manufacture has to overcome a number of technical problems to be formulated in a single dosage form. Further, the standard approach of directly mixing the active ingredients with the necessary excipients cannot be applied to combination products of different active ingredients and more sophisticated techniques are needed to separate the different active ingredients in a single dosage form.
There are various types of combination products dosage forms conceivable but it cannot be predicted which of these dosage forms best combines product stability, pharmacological efficacy, and a reliable manufacturing method. It is an object of the present invention to provide a novel tablet dosage form, which can encompass drugs of different classes which otherwise pose stability issues in a single unit.
There are several references known in the literature, which describe different techniques/methods/dosage forms combining different drugs in one unit dosage form. International Publication No. (PCT) WO 2007/043061 discloses a tablet-in-tablet system wherein two chemically incompatible anti-malarial compounds are separated by a film coating.
European Patent Application No. EP1216030A1 discloses a dosage form including a mixture of a delay release formulation of a non-steroidal anti-inflammatory drug (NSAID) and a mixture containing a prostaglandin and one or more excipients.
European Patent Application No. EP1091731 discloses a dosage form that includes a non-steroidal anti-inflammatory drug (NSAID) in coated pellets and misoprostol is located outside the pellets in the form of a solid dispersion in hydroxypropyl methylcellulose or polyvinylpyrrolidone.
U.S. Pat. Nos. 5,601,843 and 5,698,225 disclose a tablet having a core of a NSAID selected from diclofenac and piroxicam, which core is surrounded by a mantle coating of a prostaglandin such as misoprostol, wherein an intermediate coating can be present between the NSAID core and prostaglandin mantle coating.
U.S. Pat. No. 5,015,481 describes compositions that include an admixture of an NSAID selected from diclofenac and piroxicam, a prostaglandin such as misoprostol, and a stabilizer, preferably hydroxypropyl methylcellulose.
U.S. Pat. Nos. 6,183,779 and 6,287,600 disclose a dosage form that includes an NSAID present in enteric-coated granules or particles and misoprostol is located outside the pellets in the form of a solid dispersion in hydroxypropyl methylcellulose or polyvinylpyrrolidone. U.S. Pat. Nos. 6,387,410; 6,514,525; 6,537,582 and 6,787,155 disclose a similar dosage form that includes the NSAID containing pellets in a delayed release formulation.
U.S. Pat. No. 5,232,704 discloses a capsule dosage form containing one layer that includes a drug release layer containing misoprostol and the other a buoyant or floating layer.
U.S. Application No. 2005163847 discloses a solid dosage form that includes a first portion comprising NSAID; and a coating containing an antiulcerative compound, said coating at least partially surrounding the NSAID portion.
Non-steroidal anti-inflammatory drugs (NSAIDs) present a great therapeutic benefit in the treatment of inflammatory conditions such as arthritis, but have an ulcerogenic effect in the upper gastrointestinal tract, which can seriously limit their usefulness, especially for chronic treatment. Certain prostaglandin type compounds, especially prostaglandin E1 derivatives and more particularly, misoprostol have been found to mitigate or provide protection against such ulcerogenic effects when co-administered with an NSAID.
Chemical degradation of certain prostaglandin type compounds, particularly prostaglandin E1 derivatives such as misoprostol, is accelerated in the presence of water, and the primary pathway of degradation is believed to be dehydration to the corresponding prostaglandin A derivative. The problem of chemical instability becomes more acute when the prostaglandin type compound is co formulated with certain NSAIDs such as diclofenac or piroxicam.
The present invention addresses and overcomes these commonly encountered problems.